There is an urgent need for effective, non-opioid treatments for pain. Although the brain possesses pain- relieving (analgesic) circuits that are independent of endogenous opioids, little is known about substances capable of activating these systems. Dr. Lindsay Hough and colleagues at Albany Medical College discovered a novel class of non-opioid analgesic drugs derived from histamine antagonists. The prototype compound was named improgan. Improgan is highly effective in attenuating thermal and mechanical pain behaviors in rats and mice, but does not impair motor coordination or locomotor activity, and at least in limited testing, does not produce tolerance with daily dosing. Improgan's analgesic effects are not mediated by known opioid or histamine receptors. Nevertheless, improgan's actions appear to intersect with those of opioids in that focal application of improgan in the midbrain periaqueductal gray or in the rostral ventromedial medulla (RVM) produces effective antinociception. Moreover, the analgesic actions of intracerebroventricularly administered improgan are attenuated or blocked by inactivation of the RVM. Thus, improgan, like opioids, appears to activate an output from the RVM to produce its antinociceptive effect. Previous work from my laboratory has provided a number of insights into the actions of opioids in the RVM, and how these are translated into behaviorally measurable antinociception. The goal of the present experiments is to use our knowledge of opioid actions in the RVM as a framework for understanding the actions of improgan at the level of neuronal circuitry. We will use a combination of single cell recording and behavioral pharmacology to characterize the neural substrate of improgan analgesia within the RVM at the level of individual neurons and of the RVM circuit as a whole. These data will therefore provide mechanistic understanding of the link between improgan pharmacology and behavior. By comparing the neural mechanisms of this novel, non-opioid analgesic with the well-documented actions of opioids, these studies should provide new knowledge that may lead to development of clinically useful, non-opioid analgesic drugs.